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New primaquine amides with hydroxyphenyl and halogenphenyl substituents

Cancer is one of the leading causes of death worldwide [1]. Moreover, cancer is a very heterogenous disease, and cancer cells are prone to mutagenesis which leads to drug resistance. Therefore, novel and more efficient therapies are needed. Antimalarial drugs are known to exhibit antiproliferative activity, with several antimalarials in the clinical trials [2]. Almost a decade our group is focused on the synthesis and evaluation of primaquine derivatives as anticancer agents [3]. Recently, we have reported synthesis and biological activity of urea and bis-urea primaquine derivatives with hydroxyphenyl or halogenphenyl substituents, which exerted strong antiproliferative activity against a panel of tumour cell lines, with significant selectivity towards breast cancer cell line, MCF-7 [4]. This work aims at simplifying the spacer between PQ and hydroxyphenyl or halogenphenyl substituents, which would provide simpler structures and more straightforward synthesis. Synthetic pathway to PQ derivatives 3 is outlined in the Scheme and it involves three steps: coupling of PQ with monomethyl succinate, hydrolysis of the obtained methyl ester 1, and coupling of the carboxylic acid 2 with the desired aniline derivative. In both cases, coupling was achieved by the activation of carboxylic acid with 1- [bis(dimethylamino)methylene]-1H-1, 2, 3- triazolo[4, 5-b]pyridinium 3-oxid hexafluorophosphate (HATU), in the presence of N-ethyl-N, N-diisopropylamine (DIEA). All reactions were performed at room temperature, reaction times were short and synthetic yields were high. Purification of the target compounds was straightforward, and their structures were confirmed by 1H and 13C NMR, IR and MS spectroscopy.

primaquine, amides, synthesis, cancer

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